Cartilage collagen fibrils are composed of type II, type IX and type XI collagen. Mutations in the genes for any of these collagens produce cartilage disorders, which range in severity from mild dwarfism with osteoarthritis to neonatal lethal chondrodysplasias. In addition to these syndromic cartilage disorders, a growing body of evidence suggests that cartilage collagen mutations also play a role in some of the estimated 20.7 million cases of osteoarthritis in America today. Little is currently known about the etiology of the vast majority of osteoarthritis cases. But in cases where the genetic cause is known, and the mutation is not dominant negative therapeutic expression of a healthy version of the mutant gene in the affected joint may be an effective treatment. The feasibility of such a treatment for cartilage disorders has not yet been tested, but we propose to begin testing it in this project. The chondrodysplasia (cho) mouse line provides a model system in which the rescue of both chondrodysplasia and osteoarthritis by ectopic expression of a gene can be studied. The cho mutation is a single base pair deletion in Col11a1 which leads to premature termination of its protein product, the type XI collagen subunit alpha1 (XI). Mice that are homozygous for the cho mutation have severe abnormalities of all cartilaginous structures and die at birth. Mice that are heterozygous for the mutation appear normal at birth, but develop osteoarthritis within six months. The goal of this proposal is to express a Col11a1 transgene in homozygous and heterozygous cho mice, in an effort to rescue the chondrodysplasia and osteoarthritis phenotypes. Enhancer elements which are capable of directing reporter gene expression specifically to cartilage in transgenic mice have already been characterized and tested. These elements will be used to construct a transgene vector that expresses Col11a1 specifically in cartilage and at levels that approximate the expression level of the endogenous Col11a1 gene. The vector will then be used to insert the transgene in homozygous and heterozygous cho mice. Our hypothesis is that the Col11a1 transgene will rescue or ameliorate the neonatal lethal homozygous cho phenotype, allowing mice to survive beyond birth. But whether or not the mice survive beyond birth, they will be thoroughly analyzed by skeletal preparations histology, immunofluorescence, and electron microscopy. Our hypothesis in the case of the heterozygous cho mice which develop osteoarthritis by 6 months of age, is that the Col11a1 transgene will prevent or delay the onset of osteoarthritis. Histological and electron microscopic analyses of articular cartilage and intervertebral discs will be performed to assess the effects of the transgene on these mice. The overall goal of this proposal is to determine whether the chondrodysplasia and osteoarthritis phenotypes in cho mice can be rescued by the ectopic expression of a transgene, and to thereby shed light on the feasibility of one day using gene therapy protocols to treat similar disorders in humans.